Numerous devices are known to the art for delivering various drugs and other biologically active agents (hereinafter, "agent") through the skin, Representative U.S. Pat. Nos. are 3598122, 4144317, 4201211, 4262003 and 4379454, for example, which patents are hereby incorporated by reference herein. The simplest type of a transdermal delivery system comprises an agent reservoir which may be merely a mixture of a matrix material containing dissolved or dispersed agent which is maintained on the skin for a predetermined period of time by an adhesive or other means such as a strap. Matrix systems have the advantage of being easily fabricated and are generally of lower cost than more sophisticated rate controlled systems. The rate of release of an agent from a matrix however decreases as a function of t.sup.-1/2. This type of decline in release rate occurs when the agent is included in the matrix at a concentration above the saturation concentration of the agent in the matrix and becomes even more pronounced (e.g., exponential) when the agent in the supersaturated reservoir falls below saturation or is originally incorporated in the matrix at or below the saturation concentration.
For this reason it is generally desired to fabricate transdermal delivery systems with a sufficient amount of excess agent in the matrix to maintain the matrix at unit activity (or saturation) for a substantial portion of its useful life. In addition to the use of release rate controlling elements to make the release rate more constant with time, various approaches to improving the release characteristics from simple matrix type systems have been proposed. See for example, U.S. Pat. Nos. 3923939 and 4286592, which patents are incorporated herein by reference.
In certain circumstances, however, it is not only unnecessary to maintain the drug reservoir above saturation during its useful life but it is actually undesirable to do so. For example, with expensive agents it would be desirable to keep the residual agent left in the system after use to a minimum. In the case of a system in which unit activity is maintained throughout its useful life, however, the residual agent would never be present at less than the saturation concentration of the agent in the reservoir. Similarly, it is not always desirable to have a relatively constant agent input particularly when one is attempting to mimic normally fluctuating blood levels of an endogenously produced agent such as in hormone supplementation therapy or insulin administration. In these situations the normal blood levels of the agent fluctuate from a high level to a low level over various body cycle periods and agent administration would desirably parallel normal blood level cycling. The release rate from a subsaturated matrix, characterized by an initially high release rate which rapidly decays may, nevertheless, be unsuitable for even these applications and it would be desirable to provide some way for flattening out the release curve and extending the useful life of a substituted system. As used herein the term "subsaturated" shall refer to a matrix which is substantially free from any dispersped, undissolved agent and includes a matrix in which the agent may initially be at the saturation level prior to use.
According to our invention we have devised a transdermal therapeutic system employing a subsaturated agent reservoir having improved agent release characteristics. We have also provided transdermal therapeutic systems which are particularly adapted for administration of androgens such as testosterone, progestins such as estradiol, steroids such as hydrocortisone and antiviral agents such as acyclovir for example. We have also provided a transdermal therapeutic system which is particularly adapted for scrotal and labial administration of drugs.
Accordingly, it is an object of this invention to provide an improved transdermal therapeutic system utilizing a subsaturated reservoir.
It is another object of this invention to provide a transdermal therapeutic system particularly adapted for scrotal or labial delivery of drugs.
It is another object of this invention to provide a simple, inexpensive transdermal therapeutic system having improved release characteristics.